Improved protocols for microwave-assisted Cu(I)-catalyzed huisgen 1,3-dipolar cycloadditions

Article abstract of DOI:10.1135/cccc20071014

The Huisgen 1,3-dipolar cycloaddition of azides and acetylenes catalyzed by Cu(I) salts, leading to 1,2,3-triazoles, is one of the most versatile "click reactions". We have developed a series of optimized protocols and new applications of this reaction st

Full text of DOI:10.1135/cccc20071014

1014
Cintas, Martina, Robaldo, Garella, Boffa, Cravotto:
IMPROVED PROTOCOLS FOR MICROWAVE-ASSISTED
CU(I)-CATALYZED HUISGEN 1,3-DIPOLAR CYCLOADDITIONS
a
b3
Pedro CINTAS , Katia MARTINAb1, Bruna ROBALDOb2, Davide GARELLA
,
b4
b5,
Luisa BOFFA and Giancarlo CRAVOTTO
*
a
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Extremadura,
Avenida de Elvas s/n, E-06071 Badajoz, Spain; e-mail: pecintas@unex.es
Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via P. Giuria 9,
I-10125 Torino, Italy; e-mail: katia.martina@unito.it, bruna.robaldo@unito.it,
davide.garella@unito.it, luisa.boffa@unito.it, giancarlo.cravotto@unito.it
b
1
2
3
4
5
Received February 22, 2007
Accepted May 3, 2007
Dedicated to Professor Štefan Toma, a close friend and great scientist, on the occasion of his 70th
birthday.
Th e Huisgen 1,3-dipolar cycloaddition of azides an d acetylen es catalyzed by Cu(I) salts, lead-
in g to 1,2,3-triazoles, is on e of th e m ost versatile “click reaction s”. We h ave developed a se-
ries of optim ized protocols an d n ew application s of th is reaction startin g from several
substrates, com parin g h eterogen eous vs h om ogen eous catalysis, con ven tion al h eatin g vs
m icrowave irradiation or sim ultan eous m icrowave/ultrasoun d irradiation . Both n on -
con ven tion al tech n iques stron gly prom oted th e cycloaddition (brom ide → azide → triazole),
th at could be con ven ien tly perform ed in a on e-pot procedure. Th is was feasible even with
such bulky m olecules as fun ction alized β-cyclodextrin s (β-CD), startin g from 61-O-tosyl-β-CD
or from h eptakis[6-O-(tert-butyldim eth ylsilyl)]-21-O-propargyl-β-CD. “Green er” h eteroge-
n eous catalysis with ch arcoal-supported Cu(II) or Cu(I) (prepared un der ultrasoun d) was ad-
van tageously em ployed.
Keyw ord s: Click ch em istry; Microwave; Huisgen cyclization ; Heterogen eous catalysis; Ultra-
soun d; Son och em istry; Azides; Alkyn es; Triazoles; Cyclodextrin s.
Click ch em istry, in troduced by Sh arpless a few years ago1, h as em erged as
an efficien t an d tim e-savin g syn th etic m eth od. Alth ough in th eir sem in al
con tribution Sh arpless an d associates iden tified a h an dful of sim ple an d
versatile reaction s requirin g little or n o purification of products, th e
Huisgen 1,3-dipolar cycloaddition of azides an d alkyn es h as becom e th e
veritable paradigm of click reaction s. Th e classic Huisgen cycloaddition 2
leads to both 1,4- an d 1,5-disubstituted 1,2,3-triazoles, with poor or n o se-
lectivity. However, in th e Cu(I)-catalyzed click varian t, azides an d term in al
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 8, pp. 1014–1024
© 2007 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20071014

Huisgen 1,3-Dipolar Cycloadditions
1015
acetylen es react regiospecifically to give 1,4-disubstituted 1,2,3-triazoles;
th e process is widely applicable an d experim en tally straigh tforward. Th e
triazole core th us offers a un iversal m ean s of ligation an d an attractive
isosteric replacem en t in th e search for n ew leads. Th ese features are n ow
prom otin g th is powerful syn th etic tool in th e fields of polym er an d m ateri-
als scien ce, as well as drug discovery3. Th e catalyst is usually prepared in
situ by reduction of Cu(II) salts (th at are less expen sive an d often purer
th an Cu(I) salts), usually em ployin g L-ascorbic acid or sodium L-ascorbate.
Exam ples of click reaction s m ediated by h eterogen eous Cu(I) catalysis are
rare4. Recen tly Lipsh utz et al.5 foun d th at copper supported on ch arcoal
(Cu(II)/C) was an efficien t catalyst for th e Huisgen 1,3-dipolar cyclo-
addition . Van der Eycken et al.6 successfully carried out th e sam e cyclo-
addition un der m icrowave (MW) irradiation , dram atically cuttin g down th e
reaction tim e.
Th e presen t work aim ed to optim ize th e reaction protocol by com parin g
th e efficacy of soluble copper catalysts with th at of h eterogen eous catalysis
based on ch arcoal-supported Cu(II) or Cu(I). Our in vestigation also covered
role of th e solven t, effect of tem perature, an d ph ysical activation ach ieved
by exposure to MW or sim ultan eous irradiation with MW an d h igh -
in ten sity ultrasoun d (US). In oth er words, we studied th is Cu-catalyzed
th ree-com pon en t reaction un der both h om ogen eous an d h eterogen eous
con dition s in th e search for a fast an d efficien t protocol leadin g to 1,4-
disubstituted 1,2,3-triazoles. In addition , we exten ded our strategy to th e
selective fun ction alization of cyclodextrin s (CDs), a target of great practical
in terest th at we h ad already exploited for diagn ostic application s7.
Our prelim in ary trials started with ben zyl brom ide an d ph en ylacetylen e,
two con ven tion al substrates for th e Huisgen reaction , wh ich we carried out
eith er in two steps (n ucleoph ilic substitution with NaN3 followed by
cyclization ) or on e-pot reaction . Workin g in t-BuOH–H2O at 80–85 °C, we
com pared results obtain ed un der both con ven tion al h eatin g an d MW irra-
diation . We obtain ed very good yields with Cu(II) sulfate an d L-ascorbic
acid as well as un der h eterogen eous catalysis with ch arcoal-supported
Cu(II) or Cu(I). In all cases MW dram atically accelerated th e reaction . To
broaden th e scope of th is study, we perform ed th e reaction of ph en yl-
acetylen e with h eptadecyl brom ide eith er on e-pot or in two steps, th e first
on e bein g th e preparation of th e azide (Sch em e 1).
As reported in Table I, th e cyclization startin g from th e azide was carried
out in th e presen ce of Cu(II)/C an d L-ascorbic acid. MW irradiation im -
proved yields up to 83%, cuttin g th e reaction tim e down to 10 m in
(en try 2). Recyclin g of th e catalyst was feasible, an d its reuse in th e sam e
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 8, pp. 1014–1024

1016
Cintas, Martina, Robaldo, Garella, Boffa, Cravotto:
SCHEME 1
reaction afforded th e sam e yields foun d in th e first cycle, even th ough th e
reducin g agen t was om itted (en try 3); th us th e addition of L-ascorbic acid
an d Et3N to th e recycled catalyst (as recom m en ded by Lipsh utz5) could be
dispen sed with . Th is fin din g led us to in vestigate from th e very begin n in g
th e role of th e reducin g agen t. Wh en th e reaction was carried out in th e ab-
sen ce of L-ascorbic acid un der sim ple h eatin g (oil bath ), con version was
poor an d yields very low (en try 4); on th e con trary, un der MW irradiation
com plete con version took place an d an 81% yield was obtain ed after
45 m in (en try 5). Alth ough th e catalysis with Cu(I) salts was reported to re-
quire a co-solven t such as aceton itrile an d th e presen ce of an am in e8, we
TABLE I
Huisgen 1,3-dipolar cycloaddition s un der h eterogen eous catalysis
Catalyst
10 m ole %
Operatin g con dition s
85 °C
Reaction tim e
m in
Yield
%
En try
1
2
3
4
5
6
7
8
CuII/C, L-ascorbic acid
CuII/C, L-ascorbic acid
recycled CuII/Ca
CuII/C
oil bath
MW
120
10
79
83
84
30
81
78
89
93
MW
30
oil bath
MW
180
45
CuII/C
CuI/C
CuI/C
CuI/C
oil bath
MW
120
10
MW/US
10
a
Reaction carried out in th e presen ce of recycled catalyst from th e reaction listed as en try 2.
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 8, pp. 1014–1024

Huisgen 1,3-Dipolar Cycloadditions
1017
foun d th at ch arcoal-supported Cu(I) catalyzed th e reaction in t-BuOH–H2O
with out an y addition of am in e. Cu(I)/C was prepared by im pregn ation of
activated ch arcoal with CuI followin g th e Lipsh utz protocol. Cu(I)/C ca-
talysis un der MW irradiation gave excellen t results: after 10 m in th e fin al
product was isolated in 89% yield, n o furth er purification bein g required
(en try 7). A sm all im provem en t was foun d with sim ultan eous MW/US irra-
diation 9, ach ieved by in sertin g in to th e MW oven a n on -m etallic US h orn
(m ade of Pyrex, fused quartz or PEEK, i.e. poly(eth er–eth er keton e))9,10
.
Workin g un der h eterogen eous catalysis (Cu(I)/C or Cu(II)/C) MW irradia-
tion proved to be crucial for th e on e-pot reaction , wh en th e azide was gen -
erated in situ from th e correspon din g h alide (Sch em e 1). With th e
exception of h igh ly reactive ben zyl brom ide, usually th e reaction was m uch
slower com pared with stan dard click reaction s an d its rate depen ded on th e
n ature of th e alkyl brom ide. As sh own in Table II, un der MW ben zyl bro-
m ide reacted faster but th e yield was un affected. 1-Brom oh eptadecan e in
t-BuOH–H2O at 85 °C gave a very poor yield, wh ich even un der MW did
n ot reach 50%. However, th e sam e reaction , wh en perform ed un der MW ir-
radiation in DMF at 110 °C, afforded in a few m in utes th e desired product 2
in good yield (Table II, en tries 5, 6).
TABLE II
On e-pot Huisgen 1,3-dipolar cycloaddition s un der h eterogen eous catalysis (Cu(I)/C, 0.1 equiv.)
Reaction
tim e
m in
Operatin g
con dition s
Yield
%
En try
Substrate
Solven t
1
2
3
4
5
6
ben zyl brom ide
ben zyl brom ide
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
DMF
oil bath , 85 °C
MW, 85 °C
90
20
90
45
25
20
94
95
28
47
85
80
1-brom oh eptadecan e
1-brom oh eptadecan e
1-brom oh eptadecan e
1-brom oh eptadecan e
oil bath , 85 °C
MW, 85 °C
MW, 110 °C
MW/US, 110 °C
DMF
Th ese en couragin g results prom pted us to try th e syn th esis of th e cor-
respon din g bistriazole derivative from dibrom o-m-xylen e an d ph en yl-
acetylen e, as a first step towards an easy m eth od for cross-lin kin g two
acetylen ic m oieties. After som e prelim in ary trials carried out in two steps,
we turn ed to th e on e-pot reaction un der h om ogen eous catalysis, wh ich
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 8, pp. 1014–1024

1018
Cintas, Martina, Robaldo, Garella, Boffa, Cravotto:
gave product 4 in good yield (Sch em e 2). Th is procedure, usin g a soluble
Cu(II) salt, required a silica gel colum n purification for th e rem oval of cop-
per traces from th e product. Wh en Cu(II)/C was used as catalyst, th e reac-
tion tim e was lon ger an d, besides 4, a sm all am oun t of th e correspon din g
m on otriazole was also obtain ed. Because in t-BuOH–H2O ben zyl brom ide
un derwen t partial degradation , we repeated th e reaction in an h ydrous DMF
in th e presen ce of Cu(I)/C. Th e fin al product 4 was isolated in 78% yield
wh en th e process was carried out un der MW; traces of th e m on otriazole de-
rivative were form ed (Table III).
SCHEME 2
TABLE III
On e-pot Huisgen 1,3-dipolar cycloaddition s with soluble or in soluble catalyst
Reaction
tim e
m in
Catalyst
10 m ole %
Operatin g
con dition s
Yield
%
En try
Solven t
1
2
3
4
5
6
7
CuSO4, L-ascorbic acid
CuSO4, L-ascorbic acid
CuSO4, L-ascorbic acid
CuII/C, L-ascorbic acid
CuII/C, L-ascorbic acid
CuI/C
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
DMF
oil bath , 85 °C
MW, 85 °C
120
30
63
71
76
20
50
40
78
MW/US, 85 °C
oil bath , 85 °C
MW, 85 °C
20
240
30
oil bath , 110 °C
MW, 110 °C
240
30
CuI/C
DMF
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Huisgen 1,3-Dipolar Cycloadditions
1019
As th e click Huisgen cycloaddition sh ows a h igh toleran ce to m an y fun c-
tion al groups an d proceeds to com pletion in a large variety of solven ts in -
cludin g aqueous tert-butyl alcoh ol, we decided to apply it to β-cyclodextrin
(β-CD) derivatives. To th e best of our kn owledge, on ly on e exam ple of click
ch em istry con cern in g β-CD h as appeared in th e literature, viz. a copperless
MW-assisted procedure th at afforded a m ixture of h eptakis-4-[poly(ε-capro-
lacton e)]-1H-1,2,3-triazol-1-yl-β-CD an d h eptakis-5-[poly(ε-caprolacton e)]-
1H-1,2,3-triazol-1-yl-β-CD 11
.
Form ation of triazole-substituted CDs h as n ow been in vestigated un der
both h om ogen eous an d h eterogen eous Cu catalysis. To th is en d, 61-azido-
61-deoxy-β-CD an d h eptakis[6-O-(tert-butyldim eth ylsilyl)]-21-O-propargyl-
β-CD were prepared as described previously12 an d reacted with ph en yl-
acetylen e an d h eptadecyl azide, respectively (Sch em e 3). Both reaction s
were catalyzed eith er with 3% CuSO4 plus L-ascorbic acid (protocol A) or
with Cu(I)/C (protocol B). 61-Azido-61-deoxy-β-CD reacted (A) with ph en yl-
acetylen e to afford 61-deoxy-61-(4-ph en yl-1H-1,2,3-triazol-1-yl)-β-CD (6).
Th e reaction proceeded to com pletion at 80 °C in 4 h ; th e fin al product was
isolated in 73% yield by precipitation with aceton e–water. Wh en th e reac-
tion was carried out in th e presen ce of Cu(I)/C (protocol B), th e triazolyl
derivative 6 was isolated in h igh yield by filtration (Table IV, en tries 1, 2).
SCHEME 3
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 8, pp. 1014–1024

1020
Cintas, Martina, Robaldo, Garella, Boffa, Cravotto:
We also in vestigated th e feasibility of th e on e-pot reaction usin g 61-O-tosyl-
β-CD in DMF un der con ven tion al h eatin g an d MW irradiation (en tries 3,
4). Th e latter gave an overall yield of 77%.
TABLE IV
Cycloaddition s on β-CD derivatives un der h eterogen eous catalysis (Cu(I)/C, 0.1 equiv.)
Reaction
tim e
m in
Operatin g
con dition s
Yield
%
En try
Substrate
Solven t
1
2
3
4
61-azido-61-deoxy-β-CD t-BuOH–H2O
61-azido-61-deoxy-β-CD t-BuOH–H2O
oil bath , 80 °C
MW, 80 °C
90
20
94
95
31
77
61-O-tosyl-β-CD
61-O-tosyl-β-CD
DMF
DMF
oil bath , 85 °C
MW, 85 °C
240
20
We also applied our optim ized procedure to h eptakis[6-O-(tert-butyl-
dim eth ylsilyl)]-21-O-propargyl-β-CD in order to evaluate th e reactivity of
th e acetylen ic group at position 2 of β-CD. Th e reaction was perform ed
with 1-azidoh eptadecan e 1 usin g Cu(I)/C as catalyst. After 20 m in of MW
irradiation at 85 °C, con version was com plete an d com poun d 7 was isolated
in 60% yield (Sch em e 4).
SCHEME 4
In con clusion , th e presen t work dem on strates th at MW irradiation sub-
stan tially im proves th e Cu-catalyzed Huisgen cycloaddition un der both
h om ogen eous an d h eterogen eous con dition s. Bulky an d fun ction alized
m olecules such as CD derivatives are equally susceptible to triazole
cycloaddition with out appreciable loss of reactivity. Work is in progress to
evaluate th e ability of CD derivative 6 to self-assem ble by th e form ation of
in clusion com plexes between th e ph en yl group an d th e in n er cavity of th e
h ost.
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 8, pp. 1014–1024

Huisgen 1,3-Dipolar Cycloadditions
1021
EXPERIMENTAL
Com m ercially available reagen ts an d solven ts were used with out furth er purification un less
oth erwise n oted. β-CD was kin dly provided by Wacker Ch em ie (Germ an y). Reaction s were
m on itored by TLC on Merck 60 F254 (0.25 m m ) plates, wh ich were visualized by UV in spec-
tion an d/or by h eatin g after sprayin g of 5% H2SO4 in eth an ol or ph osph om olybdic acid.
Silica gel (Merck) was used for colum n ch rom atograph y (CC). Th e son och em ical apparatus
was developed in our laboratory, m odel with im m ersion h orn 13 an d a m odified cup-h orn
m odel called a “cavitatin g tube” because it features a th in titan ium tube fixed on th e tran s-
ducer14. Both reactors were equipped with efficien t coolin g system s; all critical param eters
(power, frequen cy, reaction tem perature an d com position of th e m odified atm osph ere) were
m on itored. MW-prom oted reaction s were carried out in a profession al oven , MicroSYNTH-
Mileston e (Italy). IR spectra (v in cm –1) were recorded with a Sh im adzu FT-IR 8001 spectro-
ph otom eter. Un less oth erwise stated, NMR spectra were recorded on a Bruker 300 Avan ce
(300 an d 75 MHz for 1H an d 13C, respectively) at 25 °C; ch em ical sh ifts were calibrated to
residual proton an d carbon reson an ces of th e solven ts, CDCl3 (δH 7.26, δC 77.0), DMSO-d6
(δH 2.54) an d (CD3)2CO (δH 2.05). Ch em ical sh ifts (δ) are given in ppm an d couplin g con -
stan ts (J) in Hz. Low-resolution m ass spectra were recorded on a Fin n igan -MAT TSQ70 appa-
ratus in electron im pact (EI) an d ch em ical ion ization (CI) m odes with isobutan e as reactan t
gas; ESI-MS were recorded on a Waters Microm ass ZQ apparatus equipped with ESI source.
MALDI-TOF MS were m easured on a Bruker Reflex III spectrom eter. Th e elem en tal an alysis
was determ in ed on a th erm o Electron Flash EA1112 CHNS-O An alyzer.
1-Azidoh eptadecan e (1)
Th e reaction was carried out un der m agn etic stirrin g in th e MW oven , th e tem perature be-
in g m on itored with an optical-fiber th erm om eter. 1-Brom oh eptadecan e (1 g, 3.14 m m ol)
an d sodium azide (224 m g, 3.4 m m ol) were dissolved in a m ixture of DMF–H2O (5 m l, 95:5).
Th e m ixture was irradiated with MW (200 W) at 85 °C for 15 m in , th en it was diluted with
water (25 m l) an d extracted with eth yl acetate (3 × 25 m l). Th e product was collected as a
tran sparen t oil (805 m g, 91% yield). IR: 2924, 2855, 2094 (N3), 1687, 1466, 1259. 1H NMR
(300 MHz, CDCl3): 3.26 t, 2 H, J(1,2) = 6.6 (H-1); 1.53–1.67 m , 2 H (H-2); 1.18–1.41 m , 28 H
(CH2 aliph atic); 0.887 t, 3 H, J(17,16) = 6.9 (H-17). MS (EI, m/z): 252, 112, 98. MS (CI, m/z):
282 [M + H]+, 254. For C17H35N3 (281.3) calculated: 72.54% C, 12.53% H, 14.93% N; foun d:
72.48% C, 12.21% H, 14.74% N.
1,3-Bis(azidom eth yl)ben zen e (3)
Th e reaction was carried out un der m agn etic stirrin g in th e MW oven , th e tem perature be-
in g m on itored with an optical-fiber th erm om eter. In a 25-m l two-n ecked roun d-bottom ed
flask equipped with a con den ser an d an optical-fiber th erm om eter, 1,3-bis(brom om eth yl)-
ben zen e (1 g, 3.79 m m ol) an d sodium azide (0.98 g, 15.1 m m ol) were dissolved in a m ixture
of DMF (10 m l) an d water (0.5 m l). Th e m ixture was irradiated at 100 W for 5 m in , th e tem -
perature in creased up to 80 °C. Th e reaction was m on itored by TLC (h exan e–EtOAc 9:1).
Th e reaction m ixture was diluted with EtOAc, wash ed with water (3 × 30 m l) an d brin e,
th en dried (Na2SO4) an d evaporated to give 0.47 g of 3 as a yellow oil (yield 66%). IR: 2099
(N3), 1447, 1344, 1264, 706. 1H NMR (300 MHz, CDCl3): 7.45–7.40 m , 1 H (H-5); 7.32–7.27 m ,
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 8, pp. 1014–1024

1022
Cintas, Martina, Robaldo, Garella, Boffa, Cravotto:
3 H (H-2,4,6); 4.38 s, 4 H (-N-CH2-Ph ). MS (CI, m/z): 189 [M + H]+. For C8H8N6 (188.1) cal-
culated: 51.06% C, 4.28% H, 44.66% N; foun d: 51.15% C, 4.32% H, 44.74% N.
61-Azido-61-deoxy-β-CD (5)
Th e reaction was carried out un der m agn etic stirrin g in th e MW oven , th e tem perature be-
in g m on itored with an optical-fiber th erm om eter. Sodium azide (181 m g, 2.79 m m ol) was
suspen ded in DMF (20 m l), an d 61-O-tosyl-β-CD (2 g, 1.55 m m ol) was added. Th e m ixture
was irradiated with MW at 85 °C (200 W) for 2 m in , th en aceton e (20 m l) was added an d
th e form ed precipitate was filtered. After crystallization from water–aceton e 9:1, 1.35 g of
pure 61-azido-61-deoxy-β-CD was obtain ed (75% yield). M.p. > 221 °C (dec.). IR: 3400, 2104
(N3), 1663, 1437, 1412, 1333, 1300, 1157,1030, 915. 1H NMR (300 MHz, DMSO-d6): 5.56–5.76 m ,
14 H (OH-2,3); 4.87 sh oulder, 1 H (H-1); 4.81 br s, 6 H (H-1); 4.4–4.56 m , 6 H (OH-6);
3.48–3.81 m , 28 H; 3.23–3.44 m , overlaps with H2O. MS (MALDI-TOF, m/z): 1198.59 [M +
K]+. For C42H69N3O33 (1159.4) calculated: 44.10% C, 6.08% H, 3.67% N; foun d: 44.41% C,
6.22% H, 3.74% N.
Preparation of Cu(I)/C
Activated carbon (5 g) was suspen ded with CuI (556 m g) in H2O (70 m l), th e suspen sion
was degassed an d son icated for 2 h (20.4 kHz, 150 W). Water was distilled off an d th e re-
m ain in g solid h eated to 200 °C for 20 m in . Fin ally it was wash ed with toluen e an d dried
un der vacuum .
Cu-Catalyzed Huisgen 1,3-Dipolar Cycloaddition s. Gen eral Procedure
Two-step procedure. In a 25-m l two-n ecked roun d-bottom ed flask (equipped with an
optical-fiber th erm om eter for reaction s un der MW or com bin ed MW/US) th e copper catalyst
(CuSO4 or Cu(II)/C or Cu(I)/C, both con tain in g 10 m ole % of Cu) was suspen ded in a m ixture
of t-BuOH–H2O (5 m l, 1:1). Th e alkyl azide (1 m m ol) an d th e acetylen ic derivative (1 m m ol,
if n ot oth erwise stated) were added; a furth er addition of 20 m ole % of L-ascorbic acid was
m ade on ly wh en th e catalyst was based on Cu(II). Th e m ixture was h eated or irradiated with
MW or MW/US as in dicated in th e tables. Th e reaction outcom e was m on itored by TLC un -
til com plete con version of th e startin g m aterial was observed. Wh en th e reaction was per-
form ed un der h eterogen eous catalysis, th e catalyst was filtered off, wash ed an d recovered.
Th e liquid was partially evaporated, diluted with water (20 m l), extracted with eth yl acetate
(3 × 30 m l), an d fin ally dried (Na2SO4) an d th e solven t evaporated un der vacuum .
One-pot procedure. In a 25-m l two-n ecked roun d-bottom ed flask (equipped with an
optical-fiber th erm om eter for reaction s un der MW or com bin ed MW/US), th e alkyl brom ide
or th e tosylate (1 m m ol) an d sodium azide (1.5 m m ol) were dissolved in a m ixture of
t-BuOH–H2O (5 m l, 1:1) or DMF. Wh en t-BuOH–H2O was used as solven t, th e flask was
equipped with a reflux con den ser. Th e catalyst (CuSO4 or Cu(II)/C or Cu(I)/C, both con tain -
in g 10 m ole % of Cu) an d th e acetylen ic derivative (1 m m ol) were added. L-Ascorbic acid
(20 m ole %) was added on ly wh en th e catalyst was based on Cu(II). Th e m ixture was h eated
or irradiated with MW or MW/US as in dicated in th e tables. Th e reaction outcom e was m on -
itored by TLC un til com plete con version of th e startin g m aterial an d th e azide in term ediate
was observed. Wh en th e reaction was perform ed un der h eterogen eous catalysis, th e catalyst
was filtered off, wash ed, an d recovered. Th e liquid was partially evaporated, diluted with wa-
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Huisgen 1,3-Dipolar Cycloadditions
1023
ter (20 m l), extracted with eth yl acetate (3 × 30 m l), an d fin ally dried (Na2SO4) an d evapo-
rated un der vacuum .
1-Heptadecyl-4-phenyl-1H-1,2,3-triazole (2). Th is com poun d was syn th esized usin g both
gen eral procedures an d in n o case furth er purification was n ecessary. Th e two-step proce-
dure started from 1-azidoh eptadecan e (1) an d was don e in th e presen ce of 10 m ole % of
Cu(I)/C, irradiation with MW at 85 °C for 10 m in ). Th e desired product was obtain ed in
89% yield. Th e on e-pot procedure started from 1-brom oh eptadecan e (DMF, 10 m ole % of
Cu(I)/C, irradiation with MW at 110 °C for 25 m in ). Th e desired product was obtain ed in
85% yield. M.p. 94 °C. IR: 2918, 2941, 2847, 2096 (N3), 1464, 1217, 1080, 1053, 976, 912,
841, 726, 734, 694. 1H NMR (300 MHz, CDCl3): 7.88 d, 2 H, J(2′,3′Ph ) = 7.2 (H-2′,6′ Ph );
7.74 s, 1 H (H-5); 7.21–7.45 m 3 H (H-3′,4′,5′ Ph ); 4.34 t, 2 H, J(1′,2′) = 7.2 (H-1′); 1.88–
2.01 m , 2 H (H-2′); 1.52–1.63 m , 2 H (H-3′); 1.13–1.42 m , 26 H (CH2 aliph atic); 0.88 t, 3 H,
J(17′,16′) = 6.9 (H-17′). MS (EI, m/z): 383 [M]+, 354, 172, 145. MS (CI, m/z): 384 [M + H]+.
For C25H41N3 (383.3) calculated: 78.27% C, 10.77% H, 10.95% N; foun d: 78.15% C,
10.52% H, 11.10% N.
1,3-Bis[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]benzene (4). Th is com poun d was syn th esized
usin g both gen eral procedures an d in n o case furth er purification was n ecessary. Th e
two-step procedure started from 1,3-bis(azidom eth yl)ben zen e (3) usin g acetylen ic com poun d
(2 m m ol), sodium azide (3 m m ol), 10 m ole % of Cu(II)/C an d 20 m ole % of L-ascorbic acid
(irradiation with MW at 85 °C for 20 m in ). Th e desired product was obtain ed in 85% yield.
Th e on e-pot procedure started from dibrom o-m-xylen e (10 m ole % of Cu(I)/C, irradiation
with MW at 110 °C for 30 m in ). Th e desired product was recovered in 78% yield. M.p.
145 °C. IR: 3088, 2941, 2860, 2099 (N3), 1460, 1441, 1221, 1200, 1078, 1049, 837, 820, 762,
692. 1H NMR (300 MHz, aceton e-d6): 8.37 s, 2 H (H-5); 7.86 d, 4 H, J(2′,3′Ph ) = 6.9 (H-2′,6′);
7.49–7.28 m , 10 H (H-2,4,5,6 Bz, H-3′,4′,5′ Ph ); 5.70 s, 4 H (-N-CH2-Ph ). MS (CI, m/z): 393
[M + H]+. For C24H20N6 (392.2) calculated: 73.45% C, 5.14% H, 21.41% N; foun d: 73.25% C,
5.32% H, 21.19% N.
61-Deoxy-61-(4-phenyl-1H-1,2,3-triazol-1-yl)-β-CD (6). Th is com poun d was syn th esized us-
in g both gen eral procedures an d purification specified furth er was used. Th e two-step proce-
dure started from 61-azido-61-deoxy-β-CD (5), solution of azido derivative (1 m m ol),
acetylen ic com poun d (5 m m ol) an d 10 m ole % of Cu(I)/C (irradiation with MW at 85 °C for
20 m in ). Th e catalyst was filtered off an d wash ed with water, th e filtrate was partially evapo-
rated an d precipitated with aceton e, th e product was wash ed with th e sam e solven t an d ob-
tain ed in 95% yield. Th e on e-pot procedure started from 61-O-tosyl-β-CD (DMF, 10 m ole %
of Cu(I)/C, irradiation with MW at 85 °C for 20 m in ). Th e catalyst was filtered off an d
wash ed with water, th e filtrate was partially evaporated an d precipitated with aceton e, th e
product was wash ed with th e sam e solven t an d obtain ed in 77% yield. M.p. > 235 °C (dec.).
IR: 3420, 2926, 2104 (N3), 1655, 1458, 1367, 1333, 1157, 1097, 1028, 947, 756. 1H NMR
(300 MHz, DMSO-d6): 8.52 s, 1 H (H-5′ triazole); 7.80 d, 2 H, J(2′,3′Ph ) = 7.5 (H-2′,6′ Ph );
7.42 t, 2 H, J = 7.5 (H-3′,5′ Ph ); 7.32 d, 1 H, J = 7.5 (H-4′ Ph ); 5.9–5.52 m , 14 H (OH-2,3);
4.85–4.61 m , 7 H (H-1); 4.35–4.65 m , 6 H (OH-6); 3.43–3.78 m , 28 H (H-3,5,6a,6b);
3.15–3.42 (m , overlaps with H2O). ESI-MS: 1284.3 [M + Na]+. For C50H75N3O34 (1261.4) cal-
culated: 47.58% C, 5.99% H, 3.33% N; foun d: 47.79% C, 5.72% H, 3.40% N.
Heptakis[6-O-(tert-butyldimethylsilyl)]-21-O-(1-heptadecyl-1H-1,2,3-triazol-1-yl)methyl-β-CD (7).
Th e com poun d was syn th esized from h eptakis[6-O-(tert-butyldim eth ylsilyl)]-21-O-propargyl-
β-CD (1 m m ol) by th e two-step procedure in th e presen ce of 10 m ole % of Cu(I)/C an d
1-brom oh eptadecan e (1 m m ol) (irradiation with MW at 85 °C for 20 m in ). Th e catalyst was
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1024
Cintas, Martina, Robaldo, Garella, Boffa, Cravotto:
filtered off, an d wash ed with CH2Cl2. Th e filtrate was diluted with CH2Cl2, wash ed with wa-
ter an d brin e, an d fin ally dried (Na2SO4). Th e crude residue after evaporation of th e solven t
un der reduced pressure was purified by colum n ch rom atograph y (CHCl3–CH3OH 9:1) to
yield 60% of th e desired product as a wh ite powder. M.p. 182 °C. IR: 3420, 1362, 1472,
1252, 1086, 1040, 835. 1H NMR (300 MHz, CDCl3): 4.9–4.7 m , 9 H (H-1 overlapped
triazole-CH2-O); 4.3 t, 2 H, J(1′,2′) = 6.9 (H-1′); 4.1–3.9 m , 14 H (H-3,6b); 3.78–3.6 m , 28 H
(H-2,4,5,6a); 1.8–1.7 m , 4 H (H-2′, H-3′); 1.3–1.2 m , 26 H (CH2 aliph atic); 0.88 s, 66 H (t-Bu
overlapped H-17′); 0.05 s, 42 H (Si-CH3). ESI-MS: 1145.6 [M + Na + H]2+, 1156.6 [M +
2 Na]2+. For C104H205N3O35Si7 (2252.3) calculated: 55.41% C, 9.17% H, 1.86% N, 8.72% Si;
foun d: 55.56% C, 9.21% H, 1.71% N, 8.91% Si.
We thank the MIUR-FIRB 2003 and the Ministry of Education and Science of Spain (Grant
CTQ2005-07676) for financial support. This work has been carried out under the European Union
COST Action D32/006/04.
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